(i) Field of the Invention
The present invention relates to compositions comprising an active agent. More specifically, the invention relates to active agent compositions that include a peptide and an active agent covalently attached to at least one of the N-terminus, the C-terminus, a side chain of the peptide, and/or interspersed within the peptide chain. The present invention also relates to methods for protecting and administering active agents and for treating thyroid disorders.
(ii) Description of the Related Art
In the euthyroid state, the thyroid gland is the source of two iodothyronine hormones, thyroxine (T4) and triiodothyronine (T3). Both T4 and T3 play a key role in brain development, and in the growth and development of other organ systems. The iodo-hormones also stimulate the heart, liver, kidney, and skeletal muscle to consume more oxygen, directly and indirectly influence cardiac function, promote the metabolism of cholesterol to bile acids, and enhance the lipolytic response to fat cells.
It has been estimated that the normal thyroid releases molecules of T4 and T3 in a ratio of 5:1 respectively, but other estimates in the order of 10:1 appear in the literature. It has also been reported that 20 percent of circulating T3 is released from the thyroid, while the remaining 80 percent results from the conversion of T4 to T3 by peripheral organs such as the liver. The deiodinase enzyme responsible for this conversion exists as two major isozymes. Type I deiodinase is found predominantly in the liver, kidneys, and thyroid and functions primarily to provide circulating T3, whereas Type II deiodinase acts mainly to supply intracellular T3 to the organs in which it is found, e.g., the brain and the pituitary.
The conversion of T4 to T3 involves a complex cascade of biochemical events which include substrate delivery by the bloodstream, binding and dissociation of T4 with serum proteins, capillary transit time, exposure and binding to and transport through cell membranes, intracellular transport, and the overall activity of the deiodinase enzyme responsible for the conversion. Cofactors and the competing balance between deiodination at the 5′ position and the 3′ position of T4, in turn, affect the activity of the deiodinase enzyme. Availability of the cofactor glutathione, pH, and the extent of sulfonation all influence this balance. Therefore, treating hypothyroidism with T4 alone may fail to metabolize and provide the required amount of T3 if any steps in the biochemical cascade are disrupted.
Hypothyroidism is the most common disorder of the thyroid and is manifested through the thyroid gland's inability to produce sufficient thyroid hormone. Symptoms associated with hypothyroidism include cold intolerance, lethargy, fatigue, chronic constipation and a variety of hair and skin changes. Although none of these conditions are life threatening, the disease, left untreated, could result in myxedema, coma, or death.
The cause of hypothyroidism in the U.S. is brought about by either autoimmune destruction of the thyroid tissue (Hashimoto's disease), 131I therapy, or ablative surgery. It is estimated that 8 to 10 million people in the United States have low thyroid gland function, but only about 4 to 5 million hypothyroid cases have been diagnosed and treated. The prevalence of hypothyroidism increases with age, particularly within the female population.
Currently, the most common treatment for hypothyroidism has been the administration of desiccated pig thyroid, levothyroxine sodium (T4), liothyronine sodium (T3), or a combination of T4 and T3. Unfortunately, the available treatments for hypothyroidism have several drawbacks. For instance, the use of desiccated pig thyroid raises concerns regarding its purity and potency due to its source. In addition, the use of T3 has been limited due to safety concerns raised by “spiking.” Spiking has also been known to occur with T3 in combination with T4 (sold under the trade name THYROLAR®). Furthermore, the most popular drug T4, which is a prohormone that requires metabolism to T3 in vivo for the drug to be effective, has a short shelf life. Ameliorating T4's inherent instability has been reported. U.S. Pat. No. 5,635,209 claims enhanced stability of T4 preparations through the addition of potassium iodide. U.S. Pat. No. 5,225,204 is directed to improving the stability of levothyroxine sodium. This patent indicates that the stability of the levothyroxine is affected by the presence of some carbohydrate excipients, such as dextrose, starch, sugar, and lactose. This patent claims that stability is achieved through mixing the levothyroxine with a cellulose carrier, with or without the addition of either polyvinyl pyrrolidine (PVP) or a Poloxamer. U.S. Pat. No. 5,955,105 is also directed to providing an improved, stable, solid dosage form of thyroid hormone pharmaceutical preparations. This patent claims pharmaceutical preparations of thyroxine drugs including a water-soluble glucose polymer and a partially soluble or insoluble cellulose polymer to provide the stability. The indicated stability is determined as an absence of potency loss when the preparation is stored at 40 degrees C. and 75 percent relative humidity for six months. U.S. Pat. No. 5,955,105 is hereby incorporated by reference, particularly for its teachings on components and production of pharmaceutical preparations of thyroxine drugs.
The effective delivery of a biologically active agent (active agent) is often critically dependent on the active agent delivery system used. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. Certainly, T4 would benefit from a formulation that prolongs shelf life. In addition, increasing the absorption of orally administered T4 should also reduce the potential for overdosing and shorten the titration time for patients. As mentioned above, the blunting of the T3 “spike” through a modulated release formulation would markedly improve the safety of that drug. In general, increasing the stability of any active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes, and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG), or bile acids, enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes, or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids, or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several drawbacks. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, therefore, control of the rate of release is difficult to achieve.
It is also important to control the molecular weight, molecular size, and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients, such as T4. Due to the inherent instability of non-covalent bonds, the bond between the active agent and the microsphere will usually not withstand the vigorous conditions used to reduce the composition's particle size.
U.S. application Ser. No. 09/411,238, filed Oct. 4, 1999, now Abandoned, and entitled “Use of Protein Conformation for the Protection and Release of Chemical Compounds,” hereby incorporated by reference, is directed to the manipulation of protein conformation in the protection and release of chemical compounds. The invention is based on the formation of higher-order structures that proteins assume under various salt, solvent, and pH conditions so as to protect chemical compounds and/or control the release thereof in vitro or in vivo environments.
There remains a need for compositions that effectively deliver one or more active agents synergistically. There also remains a need for compositions that protect active agents, either during storage or through the stomach. There also remains a need for methods of protecting and controlling the delivery and/or release of active agents. No attempt, heretofore reported by the inventors or elsewhere, have been made to increase the absorption of either T3 or T4 through the intestinal epithelia.
Therefore, the need still exists for a drug delivery system, which enables the use of new molecular compositions which can reduce the technical, regulatory, and financial risks associated with active agents while improving the reproducibility, bioavailability, reliability, and sustained release.